The British Journal of Pharmacology in 2006 published a paper by David A. Brown
detailed the exploration and discoveries of the physiology and pharmacology of
acetylcholine and its receptors from 1930 to 2005.
The early years
In Philadelphia in 1953 there was a symposium where the majority of papers written
about acetylcholine were authored by British physiologists and pharmacologists.
What was known in 1930?
H.H. Dale, Hunt & Taveau and A.J. Ewins were all isolating and extracting various
discoveries from ergot. Hunt & Taveau found a strong vasodepressor effect from ergot
that also was seen in acetylcholine. Eight years later, Dale proposed that the ergot extract
may contain muscarine. During this same time A.J. Ewins isolated acetylcholine which
was the active agent. Dale came to the conclusion of muscarinic and nicotinic effects
while comparing the effects of acetycholine and choline. Dale reported that certain
ethers and esters of choline demonstrated that “muscarine was paralyzed by atropine, and
nicotine was paralyzed by excess nicotine.”
Many authors wrote about the “muscarine” action found in the body showing that cranial
and sacral nerves could be stimulated involuntarily. However, at this time there was little
evidence to say that acetylcholine existed in the body.
About 2 decades later members of the British Pharmacological Society isolated
acetycholine from ox and horse spleen. A couple of other scientists previous to this
discovery identified the chemical transmission in the heart of a dog and frog proving the
inhibition from acetylcholine released from the vagus nerve to cause the heart to stop.
Dale & Dudley in 1929 wrote that the choline esters demonstrated two types of activity
which are the “muscarine” and “nicotine” effect that could be seen on the involuntarily
and voluntary muscles.
Acetycholine post-1930 (Acetycholine as a neurotransmitter)
Post-1930 discoveries and conclusions, Dale was confident that acetylcholine was found
in the body and was an important transmitter. Dale and other collaborators from 1934-
1936 stated that “acetycholine [was] a neurotransmitter from the vagus nerve to the
stomach, from sympathetic nerves to sweat glands, and at the skeletal neuromuscular
junction.” During the 1930’s technology was limiting the validity of the chemical
transmission of acetylcholine. By 1950’s the end-plate potentials demonstrated the
electrical transmission and ultimately the chemical transmission of acetylcholine to cause
motor nerve stimulation. In the mid-1950’s there was research about the acetylcholine
and choline and their respected esters in the CNS. Due to the “Dale’s Principle” many
scientists began studying the effects of acetylcholine and its antagonists on CNS activity
to apply this to drug production.
However, there was no exact indication of any specific cholinergic synapses. There are
many neurons that have nicotinic receptors but many are not involved in cholinergic
transmission. In the brain, interpeduncular nucleus (IPN) have the highest concentratio
of choline actetyltransferase and the IPN neurons have a significant amount of nicotinic
receptors as well.
Nicotine has effects on the prensynaptic receptors in addition to the many effects it has
on the brain. An example is the psychopharmacological effects which demonstrates a
release of dopamine and in turn increases the release of acetylchoine.
Postsynaptic effects are done by the muscarinic receptors which produce their effects by
the G-proteins. Responses are found to be very slow and can be excitatory and inhibitory
in nature.
Acetylcholine receptors
Nicotinic and muscarinic receptors are both stimulated by acetylcholine and also
carbachol. However there are distinct pharmacological differences between these two
receptors.
Muscarinic receptors
There are three subtypes of the muscarinic receptors. This was shown in 1968 by
Burgen & Spero on an guinea-pig intestine and also shown in rat brains. The antagonist
pirenzepine demonstrated a high-affinity in the rat brain and low-affinity in smooth
muscel and atria.
Multiple antagonists are needed to show one type of subtype and the use of subtype
gene-deficiencies experimented in mice are helpful with gene expression. There are
many central functions controlled by the muscarinic receptors such as the basal ganglion,
analgesia and hypothalamic functions.Rhodopsin is structurally and functionally similar to the muscarinic receptors.
Nicotinic receptors
Advances in nicotinic pharmacology after the 1930s showed an important
distinction between neural and muscle receptors. Drugs such as hexamethonium and
tetraethylammonium were helpful in antihypertensive pharmacotherapy.
Decamethothium blocked the nicotinic receptor at the NMJ demonstrated a new
concept called “depolaring block” which was sodium channel inactivation. While
hexamethonium demonstrated a “competitive block.”
In the CNS, acetylcholine exhibited nicotinic effects when blocked by hexamethonium.
There are many different subunit combinations as well as many physiological differences
on neurons.
There has been so much research and advancement in knowledge on nicotinic
acetycholine receptors that Dale’s nicotine action can be shown on a molecular scale.
Acetycholine release
Fatt & Katz in 1952 and Jenkinson in 1957 studied the cholingeric and neuromuscular
junction to be applied in other synapses.
The future
As scientists, there is limitations with technology but wait to show the advances in
knowledge through the use of pharmacotherapy to treat terminal diseases.
The British Journal of Pharmacology in 2006 published a paper by David A. Brown
detailed the exploration and discoveries of the physiology and pharmacology of
acetylcholine and its receptors from 1930 to 2005.
The early years
In Philadelphia in 1953 there was a symposium where the majority of papers written
about acetylcholine were authored by British physiologists and pharmacologists.
What was known in 1930?
H.H. Dale, Hunt & Taveau and A.J. Ewins were all isolating and extracting various
discoveries from ergot. Hunt & Taveau found a strong vasodepressor effect from ergot
that also was seen in acetylcholine. Eight years later, Dale proposed that the ergot extract
may contain muscarine. During this same time A.J. Ewins isolated acetylcholine which
was the active agent. Dale came to the conclusion of muscarinic and nicotinic effects
while comparing the effects of acetycholine and choline. Dale reported that certain
ethers and esters of choline demonstrated that “muscarine was paralyzed by atropine, and
nicotine was paralyzed by excess nicotine.”
Many authors wrote about the “muscarine” action found in the body showing that cranial
and sacral nerves could be stimulated involuntarily. However, at this time there was little
evidence to say that acetylcholine existed in the body.
About 2 decades later members of the British Pharmacological Society isolated
acetycholine from ox and horse spleen. A couple of other scientists previous to this
discovery identified the chemical transmission in the heart of a dog and frog proving the
inhibition from acetylcholine released from the vagus nerve to cause the heart to stop.
Dale & Dudley in 1929 wrote that the choline esters demonstrated two types of activity
which are the “muscarine” and “nicotine” effect that could be seen on the involuntarily
and voluntary muscles.
Acetycholine post-1930 (Acetycholine as a neurotransmitter)
Post-1930 discoveries and conclusions, Dale was confident that acetylcholine was found
in the body and was an important transmitter. Dale and other collaborators from 1934-
1936 stated that “acetycholine [was] a neurotransmitter from the vagus nerve to the
stomach, from sympathetic nerves to sweat glands, and at the skeletal neuromuscular
junction.” During the 1930’s technology was limiting the validity of the chemical
transmission of acetylcholine. By 1950’s the end-plate potentials demonstrated the
electrical transmission and ultimately the chemical transmission of acetylcholine to cause
motor nerve stimulation. In the mid-1950’s there was research about the acetylcholine
and choline and their respected esters in the CNS. Due to the “Dale’s Principle” many
scientists began studying the effects of acetylcholine and its antagonists on CNS activity
to apply this to drug production.
However, there was no exact indication of any specific cholinergic synapses. There are
many neurons that have nicotinic receptors but many are not involved in cholinergic
transmission. In the brain, interpeduncular nucleus (IPN) have the highest concentratio
of choline actetyltransferase and the IPN neurons have a significant amount of nicotinic
receptors as well.
Nicotine has effects on the prensynaptic receptors in addition to the many effects it has
on the brain. An example is the psychopharmacological effects which demonstrates a
release of dopamine and in turn increases the release of acetylchoine.
Postsynaptic effects are done by the muscarinic receptors which produce their effects by
the G-proteins. Responses are found to be very slow and can be excitatory and inhibitory
in nature.
Acetylcholine receptors
Nicotinic and muscarinic receptors are both stimulated by acetylcholine and also
carbachol. However there are distinct pharmacological differences between these two
receptors.
Muscarinic receptors
There are three subtypes of the muscarinic receptors. This was shown in 1968 by
Burgen & Spero on an guinea-pig intestine and also shown in rat brains. The antagonist
pirenzepine demonstrated a high-affinity in the rat brain and low-affinity in smooth
muscel and atria.
Multiple antagonists are needed to show one type of subtype and the use of subtype
gene-deficiencies experimented in mice are helpful with gene expression. There are
many central functions controlled by the muscarinic receptors such as the basal ganglion,
analgesia and hypothalamic functions.Rhodopsin is structurally and functionally similar to the muscarinic receptors.
Nicotinic receptors
Advances in nicotinic pharmacology after the 1930s showed an important
distinction between neural and muscle receptors. Drugs such as hexamethonium and
tetraethylammonium were helpful in antihypertensive pharmacotherapy.
Decamethothium blocked the nicotinic receptor at the NMJ demonstrated a new
concept called “depolaring block” which was sodium channel inactivation. While
hexamethonium demonstrated a “competitive block.”
In the CNS, acetylcholine exhibited nicotinic effects when blocked by hexamethonium.
There are many different subunit combinations as well as many physiological differences
on neurons.
There has been so much research and advancement in knowledge on nicotinic
acetycholine receptors that Dale’s nicotine action can be shown on a molecular scale.
Acetycholine release
Fatt & Katz in 1952 and Jenkinson in 1957 studied the cholingeric and neuromuscular
junction to be applied in other synapses.
The future
As scientists, there is limitations with technology but wait to show the advances in
knowledge through the use of pharmacotherapy to treat terminal diseases.
Daniel A Brown. “Acetylcholine” British Journal of Pharmacology. 2006 January; 147(S1): S120–S126.
Published online 2006 January 9. doi: http://dx.crossref.org/10.1038%2Fsj.bjp.0706474